While our multitudes of symbiotic gut bacteria perform many beneficial functions, they have been implicated as contributors to a number of diseases both within the gut and beyond. This list of diseases includes, but is certainly not limited to: inflammatory bowel disease (IBD), colorectal cancer, irritable bowel syndrome (IBS), susceptibility to enteric infections, nutritional disorders, allergy, and neuro-developmental diseases like Parkinson's disease. We have focused on the ability of some gut bacteria to utilize the glycans attached to secreted mucus and potentially cause erosion of this protective barrier. Using synthetic microbial communities assembled in gnotobiotic mice, we have shown that chronic dietary fiber deprivation promotes both increased activity and abundance of known mucus-degrading bacteria. In wild-type mice, this activity reduces the thickness of colonic mucus and promotes increased susceptibility to the enteric pathogen Citrobacter rodentium (1). While wild-type mice tolerate diet- and microbiota-induced mucus layer erosion in the absence of a pathogen, mice that are lacking normal interleukin-10 (IL-10) function develop severe inflammation in a diet-dependent fashion. Because IL-10 dysfunction is known to contribute to human IBD, we are using this model to unravel the complex mechanisms through which dietary and microbial factors conspire with human genetic defects to cause this complicated set of inflammatory diseases. In separate collaborative studies, we have used molecular genetics in B. thetaiotaomicron to implicate desulfation of host glycans as a critical pathway that contributes to inflammation in another IBD model involving IL-10 deficiency (2). Since colonic mucin glycans are heavily sulfated, these findings add additional support for the hypothesis that degradation of mucus glycans is a contributing factor in disease development. We are exploring bacterial enzymes for mucus desulfation and other catalytic steps to determine how gut bacteria break down this complicated protective barrier with the goal of blocking critical steps and preventing inflammation.